Some compounds similar to those of the present invention having a [2.2.1] or [3.1.1] bicyclic skeleton have been described as thromboxane A2 (TXA2) antagonists in the Japanese Patent Publication (Kokoku) No. 53295/1991. TXA2 is known to possess various activities such as platelet aggregation, thrombogenesis, contraction of airway smooth muscle, advance of respiratory anaphylaxis and the like. The TXA2 antagonists have, therefore, been considered to be useful as anti-thrombotic agents, anti-vasoconstrictor, anti-respiratory contractile agents as well as medicines for treating myocardial infarction or asthma. The TXA2 antagonists can be used for treating or improving conditions of diseases such as arteriosclerosis, myocardial infarction, acute myocardial ischemia angina, cardiovascular shock or preventing unexpected death and the like.
Further, other compounds similar to those of the present invention having a [2.2.1] or [3.1.1] bicyclic skeleton have been described as prostaglandin D2 (PGD2) antagonists in WO97/00853. PGD2 is a prostanoid released from mast cells in which it is produced through PGG2 and PGH2 from arachidonic acid by the action of cyclooxygenase activated by immunological or unimmunological stimulation.
PGD2 can cause strong contraction of smooth muscle of bronchus to lead to bronchial asthma, and dilate the peripheral vessels to cause an anaphylactic shook in a systemic allergic state.
Accordingly, PGD2 antagonists are useful for the improvement of conditions caused by excessive production of PGD2, particularly as medicines for treating diseases involved with mast cell dysfunction, for example, systemic mastocytosis and disorder of systemic mast cell activation as well as tracheal contraction, allergic rhinitis, allergic conjunctivitis, urticaria, itching, atopic dermatitis, alimentary allergy, ischemic reperfusion injury, cerebrovascular disorder, and inflammation.
As shown above, PGD2 receptor antagonists have a quite different character from that of TXA2 receptor antagonists in the site and mechanism of action and indications thereof.
On the other hand, a compound having a dual antagonistic activity against both a TXA2 receptor and a PGD2 receptor can be useful as therapeutic agents for various diseases caused by TXA2 or PGD2.
For example, in the case of bronchial asthma, it is known that TXA2 cause potent tracheal contraction and respiratory anaphylaxis and PGD2 effects infiltration of eosionophils. From these comprehension, TXA2 and PGD2 are thought to be one of causative substances of the pathopoiesis and advance of asthma, thus the dual antagonistic compounds are expected to be more potent agents for treating asthma than ever known antagonists.
Further, in the case of allergic rhinitis, it is recognized that TXA2 and PGD2 cause the swelling of nasal mucosa through the aggravation of vascular permeability, and PGD2 induces the nasal blockage through the enlargement of vascular volume. Therefore, the dual antagonistic compounds are expected to be more potent agents for treating nasal blockage than ever known antagonists.
These diseases and condition thereof might be treated by administering both a TXA2 receptor antagonist and a PGD2 receptor antagonist at the same time, for example, in combination therapy or as a mixture thereof. But the administration of two or more agents often causes some problems due to the difference of their metabolic rate. For example, when the antagonists are different from each other in the time to reach a maximum blood concentration or the duration of action, they do not always efficiently exhibit each receptor antagonistic effect at the same time, failing to give a desired additive or synergic effect.
It has therefore been desired to develop medicines having a dual antagonistic activity against TXA2/PGD2 receptors, which exhibit new excellent therapeutic effects and can be used for many indications.